The bacterial cell wall plays a pivotal role in maintaining the cell shape and integrity. It is also a dynamic structure that permits cell expansion and division. Compounds that interfere with the biosynthesis or integrity of this compartment are bactericidal. The bacterial cell wall is comprised of peptidoglycan (PG), a network of polysaccharide chains cross-linked by short peptides (Rogers, H. J., H. R. Perkins, and J. B. Ward, 1980, Biosynthesis of peptidoglycan. p. 239-297. In Microbial cell walls and membranes. Chapman & Hall Ltd. London). Biosynthesis of PG can be divided into three functional stages. Stage I reactions takes place in the cytoplasm and includes the activities of MurA-through MurF leading to the synthesis of PG nucleotide precursors. Stage II include membrane reactions catalyzed by Mra Y and MurG. Stage III are mediated by Penicillin-binding proteins in the periplasmic space (Bugg, T. D. H. and Walsh, C. T. 1992. Intracellular steps of bacterial cell wall peptidoglycan biosynthesis: enzymology, antibiotics, and antibiotic resistance. Nat. Prod. Rep. 9, 199-215).
A basic repeating structure of PG consists of the disaccharides N-acetylglucosamine (GlucNAc) and N-acetylmuramic acid (MurNAc). The GlucNAc and the MurNAc disaccharides are cross-linked by b-1,4-glycosidic linkages. The MurNAc is linked to a side chain of tetra- or pentapeptide consisting of L-alanine, D-glutamate, m-diaminopimelic acid and ending in either D-alanine or D-alanyl-D-alanine. Only the tetrapeptide side chain, but not the pentapeptide chain participates in cross-linking.
The successive addition of the amino acids in the above peptide chains is catalyzed by four different ligases during the cytoplasmic steps in the bisynthesis of PG. The genes encoding these enzymes are essential for growth validating each of them as antibiotic target. Several lines of evidence support the notion that these ligases are potential target for new antibiotics. These enzymes are highly specific and present in both Gram(−) and Gram (+) bacteria (Bugg, T. D. H. and Walsh, C. T. 1992.).
MurE, the meso-diaminopimelic acid-adding enzyme is an ATP-dependent amino acid ligase that is responsible for the formation of UDP-MurNAc-L-ala-D-Glu-m-Dap (Michaud C, D. Mengin-Lecreulx, J. van Heijenoort, D. Blanot. 1990. Over-production, purification and properties of the uridine-diphosphate-N-acetylmuramoyl-L-alanyl-D-glutarnate:meso-2,6-diaminopimelate ligase from Escherichia coli. Eur J Biochem 194(3):853-861). Inhibitors of this enzyme could lead to new antibiotics for treating infections with Gram (-ve) bacteria such as Pseudomonas aeruginosa. 